The goal of this project is to investigate molecular alterations in cell cycle control during neoplastic transformation. Specifically, the cellular and molecular mechanisms regulating the G1, S phase, and G2 phase checkpoint delays induced by various DNA damaging agents are being analyzed in normal diploid human fibroblasts, in human lymphoid cells, and in human cells with genetic alterations in cell cycle checkpoint genes and in cancer susceptibility genes, such as the gene mutated in the heritable cancer syndrome ataxia telangiectasia (ATM). Studies are underway to characterize the function of the ATM and the related ATR protein kinases and the molecular events critical in cell cycle checkpoint signaling following exposures to ionizing radiation (IR), ultraviolet radiation (UV), reactive oxygen species and other environmental stresses. These investigations involve studies of the function and regulation of these protein kinases in cell cycle checkpoint signal transduction pathways. In addition, studies utilizing microarray analyses are ongoing to examine gene expression in normal cells and in cells from patients with heritable cancer susceptibility syndromes following exposure to environmental insults, with the goal of better understanding critical cellular responses to environmental toxicants and to potentially identify novel genes regulated in response to the insults that may play a critical role in cell survival/death or neoplastic transformation following exposures.